Advanced glycation end products (AGEs) are formed by a complex chain of reactions between reducing sugar such as glucose with proteins, resulting in the formation of multimeric complexes that trigger several pathological events (Pathak et al; Eur J Med Res (2008) 13: 388-398).
Advanced glycation end products (AGEs) have been implicated in the pathogenesis of a variety of debilitating diseases such as complications of diabetes, atherosclerosis, Alzheimer's and Rheumatoid arthritis, as well as in the normal aging process. In diabetes, where blood glucose level is significantly higher than normal, the reaction of glucose with several proteins such as haemoglobin and collagen, gives rise to the formation of AGE, which in turn, is responsible for the complications associated with diabetes, such as nephropathy, neuropathy, microangiopathy, endothelial dysfunction and other organ dysfunctions. In addition, the activity of several growth factors, such as basic fibroblast growth factor, is also impaired. AGE products, unlike normal proteins in tissue, have a slower rate of turnover and replenishment. It has been reported that AGE products may in fact elicit a complex immunological reaction involving RAGE (Receptor for Advanced Glycation End Products) and activation of several incompletely defined immunological processes. It has been documented that diabetes with evidence of microangiopathy and macroangiopathy also show evidence of oxidative stress, the mechanism of which has not been elucidated. (Stehouwer et al; Cardiovascular Research 1997; 34:55-68 and Smit et al.; Current Medicinal Chemistry 2004; 11:2767-84). Due to the clinical significance of AGE formation, several successful therapeutic approaches have been tried based upon intervening in the accumulation of AGEs. One of the approaches is to inhibit the formation of AGEs from its precursors, by the administration of therapeutic agents. In another approach for controlling levels of AGEs in tissues, therapeutic agent is administered which can reverse or break AGE cross-links, especially in those tissues in which AGE cross-links have already accumulated to levels which are responsible for subclinical or clinical pathology.
EP1243581, EP1222171 and EP1373263 describe pyridinium derivatives as AGE inhibitor or AGE breaker for management of complications associated with diabetes and aging related disorders.
Joline et al discloses pyridoxamine class of compounds as AGE inhibitors for treatment of diabetic nephropathy, and concluded that pyridoxamine compounds should be tested for safety profile when used for treatment of diabetes. (J Am Soc Nephrol 2012; 3: 6-8)
Though prior art provides various AGE inhibitor and the compounds having dual activity including AGE inhibition and AGE breaking; none of the AGE specific molecule has yet been reached to advanced clinical stage. There exists a need of new therapeutic molecules which are safe and effective in treating and controlling various pathologies caused due to formation and accumulation of AGE.
Present invention provides novel pyridinium compounds as AGE inhibitor and AGE breaker, which have demonstrated improved efficacy with desired safety profile.